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Antimicrobial Agents and Chemotherapy Feb 2020Suramin is 100 years old and is still being used to treat the first stage of acute human sleeping sickness, caused by Suramin is a multifunctional molecule with a wide... (Review)
Review
Suramin is 100 years old and is still being used to treat the first stage of acute human sleeping sickness, caused by Suramin is a multifunctional molecule with a wide array of potential applications, from parasitic and viral diseases to cancer, snakebite, and autism. Suramin is also an enigmatic molecule: What are its targets? How does it get into cells in the first place? Here, we provide an overview of the many different candidate targets of suramin and discuss its modes of action and routes of cellular uptake. We reason that, once the polypharmacology of suramin is understood at the molecular level, new, more specific, and less toxic molecules can be identified for the numerous potential applications of suramin.
Topics: Animals; Humans; Suramin; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosomiasis, African
PubMed: 31844000
DOI: 10.1128/AAC.01168-19 -
Nature Oct 2022Filoviruses, including Ebola virus, pose an increasing threat to the public health. Although two therapeutic monoclonal antibodies have been approved to treat the Ebola...
Filoviruses, including Ebola virus, pose an increasing threat to the public health. Although two therapeutic monoclonal antibodies have been approved to treat the Ebola virus disease, there are no approved broadly reactive drugs to control diverse filovirus infection. Filovirus has a large polymerase (L) protein and the cofactor viral protein 35 (VP35), which constitute the basic functional unit responsible for virus genome RNA synthesis. Owing to its conservation, the L-VP35 polymerase complex is a promising target for broadly reactive antiviral drugs. Here we determined the structure of Ebola virus L protein in complex with tetrameric VP35 using cryo-electron microscopy (state 1). Structural analysis revealed that Ebola virus L possesses a filovirus-specific insertion element that is essential for RNA synthesis, and that VP35 interacts extensively with the N-terminal region of L by three protomers of the VP35 tetramer. Notably, we captured the complex structure in a second conformation with the unambiguous priming loop and supporting helix away from polymerase active site (state 2). Moreover, we demonstrated that the century-old drug suramin could inhibit the activity of the Ebola virus polymerase in an enzymatic assay. The structure of the L-VP35-suramin complex reveals that suramin can bind at the highly conserved NTP entry channel to prevent substrates from entering the active site. These findings reveal the mechanism of Ebola virus replication and may guide the development of more powerful anti-filovirus drugs.
Topics: Antiviral Agents; Catalytic Domain; Cryoelectron Microscopy; DNA-Directed RNA Polymerases; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Protein Subunits; RNA, Viral; Suramin; Viral Regulatory and Accessory Proteins; Virus Replication
PubMed: 36171293
DOI: 10.1038/s41586-022-05271-2 -
Communications Biology Apr 2023SARS-CoV-2 receptor binding domains (RBDs) interact with both the ACE2 receptor and heparan sulfate on the surface of host cells to enhance SARS-CoV-2 infection. We show...
SARS-CoV-2 receptor binding domains (RBDs) interact with both the ACE2 receptor and heparan sulfate on the surface of host cells to enhance SARS-CoV-2 infection. We show that suramin, a polysulfated synthetic drug, binds to the ACE2 receptor and heparan sulfate binding sites on the RBDs of wild-type, Delta, and Omicron variants. Specifically, heparan sulfate and suramin had enhanced preferential binding for Omicron RBD, and suramin is most potent against the live SARS-CoV-2 Omicron variant (B.1.1.529) when compared to wild type and Delta (B.1.617.2) variants in vitro. These results suggest that inhibition of live virus infection occurs through dual SARS-CoV-2 targets of S-protein binding and previously reported RNA-dependent RNA polymerase inhibition and offers the possibility for this and other polysulfated molecules to be used as potential therapeutic and prophylactic options against COVID-19.
Topics: Humans; SARS-CoV-2; COVID-19; Suramin; Angiotensin-Converting Enzyme 2; Spike Glycoprotein, Coronavirus; Heparitin Sulfate
PubMed: 37031303
DOI: 10.1038/s42003-023-04789-z -
Bulletin of the World Health... 1978Well over 20 million people in the world are infected with Onchocerca volvulus and it is probable that 200 000-500 000 people are blind as a result of this infection,...
Well over 20 million people in the world are infected with Onchocerca volvulus and it is probable that 200 000-500 000 people are blind as a result of this infection, which is the most important cause of blindness in certain areas of Africa and Latin America.Treatment of the disease is difficult and often produces serious adverse reactions in the patient. Combined use of diethylcarbamazine citrate and suramin is still the most suitable form of treatment. Screening for the early detection of cases at high risk of ocular manifestations must be organized, and their treatment undertaken, if blindness is to be avoided.Prevention of ocular onchocerciasis is feasible, using vector control methods to reduce transmission, but the procedures are costly and may have to be maintained for many years.Research is needed to improve treatment and to find a chemoprophylactic agent or a preventive vaccine.
Topics: Diethylcarbamazine; Drug Therapy, Combination; Eye Diseases; Humans; Insect Control; Onchocerciasis; Suramin
PubMed: 307448
DOI: No ID Found -
Mitochondrion Nov 2018Are the symptoms of autism caused by a treatable metabolic syndrome that traces to the abnormal persistence of a normal, alternative functional state of mitochondria? A... (Review)
Review
Are the symptoms of autism caused by a treatable metabolic syndrome that traces to the abnormal persistence of a normal, alternative functional state of mitochondria? A small clinical trial published in 2017 suggests this is possible. Based on a new unifying theory of pathogenesis for autism called the cell danger response (CDR) hypothesis, this study of 10 boys, ages 5-14years, showed that all 5 boys who received antipurinergic therapy (APT) with a single intravenous dose of suramin experienced improvements in all the core symptoms of autism that lasted for 5-8weeks. Language, social interaction, restricted interests, and repetitive movements all improved. Two children who were non-verbal spoke their first sentences. None of these improvements were observed in the placebo group. Larger and longer studies are needed to confirm this promising discovery. This review introduces the concept of M2 (anti-inflammatory) and M1 (pro-inflammatory) mitochondria that are polarized along a functional continuum according to cell stress. The pathophysiology of the CDR, the complementary functions of M1 and M2 mitochondria, relevant gene-environment interactions, and the metabolic underpinnings of behavior are discussed as foundation stones for understanding the improvements in ASD behaviors produced by antipurinergic therapy in this small clinical trial.
Topics: Administration, Intravenous; Adolescent; Autistic Disorder; Child; Child, Preschool; Clinical Trials as Topic; Humans; Male; Mitochondria; Placebos; Purinergic Antagonists; Suramin; Treatment Outcome
PubMed: 29253638
DOI: 10.1016/j.mito.2017.12.007 -
Viruses May 2021Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally...
Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CL). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CL but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CL. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.
Topics: Antiviral Agents; COVID-19 Vaccines; Coronavirus 3C Proteases; Cysteine Endopeptidases; Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Protease Inhibitors; Quinacrine; SARS-CoV-2; Suramin; Viral Nonstructural Proteins; COVID-19 Drug Treatment
PubMed: 34068686
DOI: 10.3390/v13050873 -
Lipids in Health and Disease Dec 2023Previous studies demonstrated that mast cells with their degranulated component heparin are the major endogenous factors that stimulate preadipocyte differentiation and...
BACKGROUND
Previous studies demonstrated that mast cells with their degranulated component heparin are the major endogenous factors that stimulate preadipocyte differentiation and promote fascial adipogenesis, and this effect is related to the structure of heparin. Regarding the structural and physiological properties of the negatively charged polymers, hexasulfonated suramin, a centuries-old medicine that is still used for treating African trypanosomiasis and onchocerciasis, is assumed to be a heparin-related analog or heparinoid. This investigation aims to elucidate the influence of suramin on the adipogenesis.
METHODS
To assess the influence exerted by suramin on adipogenic differentiation of primary white adipocytes in rats, this exploration was conducted both in vitro and in vivo. Moreover, it was attempted to explore the role played by the sulfonic acid groups present in suramin in mediating this adipogenic process.
RESULTS
Suramin demonstrated a dose- and time-dependent propensity to stimulate the adipogenic differentiation of rat preadipocytes isolated from the superficial fascia tissue and from adult adipose tissue. This stimulation was concomitant with a notable upregulation in expression levels of pivotal adipogenic factors as the adipocyte differentiation process unfolded. Intraperitoneal injection of suramin into rats slightly increased adipogenesis in the superficial fascia and in the epididymal and inguinal fat depots. PPADS, NF023, and NF449 are suramin analogs respectively containing 2, 6, and 8 sulfonic acid groups, among which the last two moderately promoted lipid droplet formation and adipocyte differentiation. The number and position of sulfonate groups may be related to the adipogenic effect of suramin.
CONCLUSIONS
Suramin emerges as a noteworthy pharmaceutical agent with the unique capability to significantly induce adipocyte differentiation, thereby fostering adipogenesis.
Topics: Rats; Animals; Adipogenesis; Suramin; Antiparasitic Agents; Cell Differentiation; Adipocytes, White; Heparin
PubMed: 38093311
DOI: 10.1186/s12944-023-01980-3 -
The Journal of Biological Chemistry Jul 2020Inositol hexakisphosphate (IP) is an abundant metabolite synthesized from inositol 1,3,4,5,6-pentakisphosphate (IP) by the single IP 2-kinase (IP5K). Genetic and...
Inositol hexakisphosphate (IP) is an abundant metabolite synthesized from inositol 1,3,4,5,6-pentakisphosphate (IP) by the single IP 2-kinase (IP5K). Genetic and biochemical studies have shown that IP usually functions as a structural cofactor in protein(s) mediating mRNA export, DNA repair, necroptosis, 3D genome organization, HIV infection, and cullin-RING ligase (CRL) deneddylation. However, it remains unknown whether pharmacological perturbation of cellular IP levels affects any of these processes. Here, we performed screening for small molecules that regulate human IP5K activity, revealing that the antiparasitic drug and polysulfonic compound suramin efficiently inhibits IP5K and The results from docking experiments and biochemical validations suggested that the suramin targets IP5K in a distinct bidentate manner by concurrently binding to the ATP- and IP-binding pockets, thereby inhibiting both IP phosphorylation and ATP hydrolysis. NF449, a suramin analog with additional sulfonate moieties, more potently inhibited IP5K. Both suramin and NF449 disrupted IP-dependent sequestration of CRL by the deneddylase COP9 signalosome, thereby affecting CRL activity cycle and component dynamics in an IP5K-dependent manner. Finally, nontoxic doses of suramin, NF449, or NF110 exacerbate the loss of cell viability elicited by the neddylation inhibitor and clinical trial drug MLN4924/pevonedistat, suggesting synergistic ef-fects. Suramin and its analogs provide structural templates for designing potent and specific IP5K inhibitors, which could be used in combination therapy along with MLN4924/pevonedistat. IP5K is a potential mechanistic target of suramin, accounting for suramin's therapeutic effects.
Topics: Benzenesulfonates; Cullin Proteins; Cyclopentanes; Enzyme Inhibitors; HCT116 Cells; HEK293 Cells; Humans; Neoplasm Proteins; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Phytic Acid; Pyrimidines; Suramin
PubMed: 32493769
DOI: 10.1074/jbc.RA120.014375 -
Viruses Aug 2021In 2021, we commemorate the 40th anniversary of the identification of the disease AIDS, the acquired immune deficiency syndrome, a name that for the first time in...
In 2021, we commemorate the 40th anniversary of the identification of the disease AIDS, the acquired immune deficiency syndrome, a name that for the first time in history was launched in 1981 [...].
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Discovery; HIV; History, 20th Century; History, 21st Century; Humans; Suramin
PubMed: 34452510
DOI: 10.3390/v13081646 -
Parasitology Research Dec 2023Suramin was the first drug developed using the approach of medicinal chemistry by the German Bayer company in the 1910s for the treatment of human African sleeping... (Review)
Review
Suramin was the first drug developed using the approach of medicinal chemistry by the German Bayer company in the 1910s for the treatment of human African sleeping sickness caused by the two subspecies Trypanosoma brucei gambiense and Trypanosoma brucei rhodesienese. However, the drug was politically instrumentalized by the German government in the 1920s in an attempt to regain possession of its former African colonies lost after the First World War. For this reason, the formula of suramin was kept secret for more than 10 years. Eventually, the French pharmacist Ernest Fourneau uncovered the chemical structure of suramin by reverse engineering and published the formula of the drug in 1924. During the Nazi period, suramin became the subject of colonial revisionism, and the development of the drug was portrayed in books and films to promote national socialist propaganda. Ever since its discovery, suramin has also been tested for bioactivity against numerous other infections and diseases. However, sleeping sickness caused by Trypanosoma brucei rhodesiense is the only human disease for which treatment with suramin is currently approved.
Topics: Animals; Humans; Suramin; Trypanosomiasis, African; Trypanosoma brucei rhodesiense; Trypanosoma brucei brucei
PubMed: 38057659
DOI: 10.1007/s00436-023-08027-7